Importance: COVID-19 has not impacted people or countries uniformly. This disparity has prompted investigations to identify clinical and genetic predictors of COVID-19 mortality. Headache, a COVID-19 symptom, has been associated with positive disease prognosis. It is logical to consider whether primary headache disorders, among the most prevalent and disabling diseases globally, may also be associated with reduced viral mortality and thereby may have arisen as adaptive host defences. Objective: To study the relationship between COVID-19 mortality and primary headache disorders. Main outcome measure: Using a generalized additive model regression (GAM), we analysed data across 171 nations to identify variables which impact COVID-19 mortality rates (demographics, national wealth and government effectiveness, pandemic management indexes, latitude of the country's capital, prevalence of headache disorders and other diseases). We performed similar analyses of seasonal influenza mortality. Separately, we meta-analysed studies of COVID-19 inpatient survival reporting headache, using PRISMA guidelines. Results: In the global population-level analysis, we observed that a higher prevalence of headache disorders was associated with a higher COVID-19 mortality rate, and represented the main variable contributing to differences in COVID-19 mortality rates between countries (37.8%; F value=10.68). By contrast, we observed a negative trend between the prevalence of headache disorders and influenza death rates. Controversially, when considering headache as a symptom of COVID-19, in the 48 meta-analysed studies we observed a significantly higher risk ratio of survival (RR:2.178 [1.882-2.520], p<0.0001) among COVID-19 inpatients with headache. Conclusions and Relevance: Headache as a primary disorder is more prevalent in nations with higher COVID-19 mortality, whereas headache as a COVID-19 symptom is associated with enhanced survival. Further studies should clarify whether primary headache disorders represent a risk factor for mortality for COVID-19 or, rather, whether this association reflects evolutionary adaptive processes to enhance survival that, in the case of COVID-19, are insufficiently protective.

ObjectiveTo assess saliva as a substrate to measure CGRP by comparing interictal levels of CGRP in patients with episodic migraine and controls; and to evaluate saliva CGRP temporal profile during migraine attacks.MethodsThis prospective observational study included women with episodic migraine and healthy controls. Participants collected daily saliva samples for 30 consecutive days and 3 additional ones during migraine attacks. 4 timepoints were considered: interictal (72h headache-free), preictal (PRE-24h before the attack), ictal (0h,2h,8h), postictal (POST-24h after the attack). CGRP levels were quantified by ELISA.Results35 women (22 patients, 13 controls) were included. Statistically significant differences were found in interictal salivary levels of CGRP between patients and controls (median[IQR]: 98.0 [86.7] vs. 42.2 [44.7] pg/mL; p=0.010). An increase in CGRP levels during migraine attacks was detected (median[IQR]: preictal 113.5 [137.8], 0h 164.6 [204.5], 2h 101.7 [159.1], 8h 82.6 [166.2], postictal 79.6 [124.3] pg/ml; p<0.001). Patients were classified as having CGRP-dependent (80.0%) and non-CGRP dependent migraine attacks (20.0%) according to the magnitude of change between preictal and ictal phase (0h). Accompanying symptoms were different depending on the type of attack. In the longitudinal analysis, we observed that the amount of CGRP measured during attacks were phase dependent and it was influenced by the frequency of monthly headache days (p=0.02).InterpretationPatients with episodic migraine have higher interictal salivary levels of CGRP than controls. These levels usually increase during a migraine attack, however, not every attack is CGRP-dependent, which in turn, might explain different underline pathophysiology and response to acute and preventive treatment.

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